Introduction and Aims: Nowadays, the main focus in the management of chronic kidney disease (CKD) patients has been as early as possible detection, with an intention to prevent or at least slow down the disease progression. However, an increase in the slope of the estimated glomerular filtration rate (eGFR) over time may be observed in a substantial proportion of patients, where the true GFR improvement has been also confirmed by direct measurement of kidney function. Nevertheless, there is still a dilemma weather improvement in eGFR means improvement in renal function. In this study, we aimed to identify urinary peptide markers associated with improvement in eGFR and possibly explain the underlying reasons for such outcomes.
Methods: Human Urinary Proteome database was generated by applying capillary electrophoresis coupled to mass spectrometry (CE-MS) technology. From this database we extracted the available clinical/biochemical and CE-MS data from 2263 patients with baseline eGFR in between 16-89 mL/min/1.73 m2. We calculated %slope/year of eGFR by linear regression using all recorded serum creatinine measurements over 3 years of follow-up. Patients with lower than -5% slope/year were described as progressors, those with %slope/year between -1.5% and +1.5% as stable and patients with > 5% slope/year as patients with improvement of eGFR. Three subsequent statistical analyses were performed, comparing different patient groups: 1) progressors vs. patients with improvement, 2) stable vs. improvement and 3) progressors vs. stable.
Results: There was no significant difference with regard to the baseline eGFR when the groups were stratified according to the %change of eGFR slope per year. Our initial Venn diagram analysis revealed 8 peptides that were overlapping i.e. detected in each of the above mentioned analysis, 5 of which were identified using liquid chromatography coupled with mass spectrometry (LC-MS/MS). Four uromodulin fragments were found to be upregulated in patients with improvement, where peptide fragment corresponding to clusterin was downregulated in the same patient group.
Conclusions: The improvement in eGFR over time that was associated with several peptide fragments of uromodulin may be due to its protective function, enabling patients to preserve and/or improve their kidney function. The second most abundant protein in our study, clusterin, induced during renal and other tissue injuries has been associated with the progression of CKD as a significant predictor of GFR decline. With the upregulation of the uromodulin and downregulation of the clusterin fragments in the baseline urine output of patients with improvement in eGFR over time, we may conclude these patients were predisposed to improve not only their eGFR but also their kidney function, which can’t be predicted by regular clinical management. Our identified biomarkers, associated with improvement in kidney function, may provide a better insight into the disease pathogenesis and enable identifying patients predisposed to improve and treating them with an appropriate specific, supportive or less aggressive therapy.
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